Robert Carlone

Professor, Biological Sciences

We study the role of retinoids such as all-trans (atRA) and 9-cis retinoic acids in neuronal growth, development and regeneration in both vertebrate and invertebrate model systems. We use the spinal cord of the adult newt (Notophthalmus viridescens) to examine the role of atRA in a system capable of epimorphic regeneration into adulthood.

We have found that atRA can promote neurite outgrowth and direct growth cone turning in cultured newt spinal cord explants and that this small molecule works through the specific nuclear receptor, retinoic acid receptor beta 2 (RARβ2). We have cloned the newt homolog of RARβ2 and have determined that, unlike in adult mammalian spinal cord tissue, expression of the newt receptor is maintained in normal spinal cord in the adult and upregulated after spinal cord injury. We most recently are involved in studies to determine the precise function of atRA signaling in this process and to identify putative upstream regulators and downstream targets of this pathway required for regeneration of the cord. We have identified two microRNAs, miR-133a and miR-21, involved in regulating RARβ2 synthesis in the ependymoglial cells of the caudal spinal cord.

In collaboration with Gaynor Spencer in our department, we have extended our studies on the role of these retinoids in promoting and guiding outgrowth of isolated, identifiable neurons from the brain of the pond snail (Lymnaea stagnalis). We have provided evidence that both atRA and 9-cis RA can promote survival and outgrowth as well as provide directional cues in vitro for visceral F neurons and Pedal A ciliary motorneurons. Most recently we have provided strong evidence that these retinoids are acting via a novel non-genomic mechanism to elicit growth cone turning in these neurons, since turning in response to an applied gradient of atRA can still occur in isolated growth cones surgically removed from their cell bodies and nuclei. Studies are underway to decipher the precise mechanisms underlying this non-genomic form of retinoid signaling. These include an examination of the role of miR-124 in the regulation of local (growth cone specific) protein synthesis as cells respond chemotactically to a gradient of retinoic acid.